Parkinsonism (MIM168600) is a clinical syndrome characterized by bradykinesia, resting tremor, muscle rigidity, and postural instability (Gelb et al. 1999). The most common cause of parkinsonism is Parkinson's disease (PD). Second to Alzheimer's disease, PD is the most common neurodegenerative disorder affecting >1% of the population over 55 years of age (de Rijk et al. 1995). Neuropathological findings in PD are loss of pigmented neurons in the brainstem, substantia nigra and locus ceruleus, with intracellular Lewy body inclusions found within surviving neurons (Forno 1996).
Although PD is considered a sporadic disease, various hereditary forms of parkinsonism have been recognized (Vila and Przedborski 2004). A major breakthrough in recent years has been the mapping and cloning of a number of genes causing monogenic forms of parkinsonism. Genomic multiplication and missense mutations in the α-synuclein gene were initially identified in a small number of families with autosomal dominant parkinsonism (PARK1/4 [MIM 168601]) (Polymeropoulos et al. 1997; Kruger et al. 1998; Singleton et al. 2003; Chartier-Harlin et al. 2004; Farrer et al. 2004; Zarranz et al. 2004). Subsequently, α-synuclein antibodies were found to robustly stain Lewy bodies and Lewy neurites in the substantia nigra in familial and sporadic PD (Spillantini et al. 1997) and common genetic variability in the α-synuclein promoter has been implicated in sporadic PD (Pals et al. 2004).
Autosomal recessive mutations in three genes, parkin, DJ-1 and PINK1 have been linked with early-onset parkinsonism (<45 years at onset) (PARK2, PARK6 & PARK7 [MIM 602533, 602544 & 608309]) (Kitada et al. 1998; Bonifati et al. 2003; Valente et al. 2004). A large number of pathogenic mutations and rearrangements have been identified in the parkin gene reviewed by (Mata et al. 2004), but mutations in DJ-1 and PINK-1 are rare (unpublished data).
Very recently, five pathogenic mutations were identified in a gene, leucine-rich repeat kinase 2 (LRRK2) in six families with autosomal-dominant parkinsonism, linked to the PARK8 locus [MIM 607060]) (Zimprich et al. 2004a). Paisan-Ruiz and colleagues independently confirmed these findings of two pathogenic mutations in a British and Basque families (Paisan-Ruiz et al. x2004).